bims-mecosi 2025-12-14 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–12–14
fifteen papers selected by
Verena Kohler, Umeå University

The role of mitochondrial-associated endoplasmic reticulum membranes (MAMs) in diabetic microvascular complications: a review.
Role of mitochondria-associated membranes (MAMs) in inflammatory signaling: implications for acute lung injury pathogenesis.
Communication between chloroplasts and the endoplasmic reticulum in plants under abiotic stress.
Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.
[Research advances on mitochondria-associated endoplasmic reticulum membrane in pulmonary hypertension].
Hinge sites in the lipid transfer channel modulate function of the yeast bridge-like transfer protein Vps13.
Integrated approaches for multiscale mitochondrial structure and function analysis.
GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.
Prepuberty exposure to polystyrene nanoplastics induces cardiac inflammation through calcium overload-mediated ROS/JAK1/STAT3 signaling cascade.
Dual-pathway mechanism of vanadium-induced hepatotoxicity in ducks: Synergistic crosstalk between glucose homeostasis disruption and NADH/FSP1/COQ10 axis-driven ferroptosis.
Crosstalk Between the Endoplasmic Reticulum and Mitochondria in Skeletal Muscle: Implications for Meat Quality.
EGCG attenuates Cd reproductive toxicity in Caenorhabditis elegans by modulating ER-mitochondrial interactions.
PINK1/Parkin promotes liver regeneration via Sigma-1 ubiquitination to inhibit ER-Mitochondrial calcium transfer.
MARCH5-mediated MIEF2 ubiquitination and degradation contribute to gigantol to against hepatic steatosis and mitochondrial fission in alcoholic liver disease.
ED-71 prevents glucocorticoid-induced bone loss by inhibiting type H vascular endothelial cell senescence through maintaining mitochondria-associated membrane-mediated calcium homeostasis.

Cell Death Dis. 2025 Dec 09.

The role of mitochondrial-associated endoplasmic reticulum membranes (MAMs) in diabetic microvascular complications: a review.

Yudian Wang, Yufei Zhang, Qi Jin, Hailing Zhao, Ping Li.

Diabetic vascular complications include macrovascular lesions and microvascular lesions. Diabetic microvascular complications (DMC) are mainly manifested by microvascular endothelial dysfunction, basement membrane thickening, capillary permeability changes and microthrombosis, which may contribute to the occurrence of kidney, cardiac, ocular and peripheral system damage in diabetic individuals. Thus, it is urgent to develop new prevention and treatment strategies. The mitochondria-associated endoplasmic reticulum membranes (MAMs), as a highly heterogeneous membrane contact site, play a key role in maintaining biological communication between the endoplasmic reticulum (ER) and mitochondria. Studies have shown that MAMs are involved in the pathogenesis of DMC by regulating Ca2+ homeostasis, lipid synthesis and transport, mitochondrial dynamics, ER stress, glucose homeostasis, autophagy, apoptosis, and inflammation. This review comprehensively summarizes the complex structure and key biological functions of MAMs that drive the physiological transmission of substances and signals between organelles. Furthermore, we focused on exploring the regulatory mechanism of MAMs on different diabetic microangiopathies, including diabetic kidney disease (DKD), diabetic cardiomyopathy (DCM), and diabetic retinopathy (DR). In conclusion, targeting MAMs is a promising but challenging therapeutic strategy.

DOI: https://doi.org/10.1038/s41419-025-08236-1
Front Cell Dev Biol. 2025 ;13 1690934

Role of mitochondria-associated membranes (MAMs) in inflammatory signaling: implications for acute lung injury pathogenesis.

Huifeng Qian, Guanguan Qiu, Jianguo Xu, Guoping Zheng.

  Mitochondria-associated membranes (MAMs), the specialized contact regions linking the endoplasmic reticulum (ER) and mitochondria, have emerged as dynamic communication hubs critical for preserving cellular homeostasis. These structures are crucial for controlling a range of essential cellular processes, such as calcium (Ca2+) signaling, lipid metabolism, autophagy, apoptosis, and inflammatory response. Increasing evidence connects MAM dysfunction to various inflammatory conditions, such as metabolic disorders, neurodegenerative diseases, and antiviral response. In the context of acute lung injury, altered ER-mitochondria interactions can result in mitochondria Ca2+ overload, heightened oxidative stress, and augmented inflammatory response. Together, these pathological processes enhance endothelial permeability and exacerbate pulmonary inflammation. This review highlights the structural and functional attributes of MAMs, the mechanisms underlying MAM-mediated inflammation, and the roles of MAMs in metabolic, neurological, and antiviral inflammation. It also delves into the role of MAMs in acute lung injury, unveiling fresh insights that may pave the way for innovative therapies targeting ER-mitochondria crosstalk.

Keywords:  acute lung injury; endoplasmic reticulum; inflammation; mitochondria; mitochondria-associated membranes (MAMs)

DOI:  https://doi.org/10.3389/fcell.2025.1690934
Trends Plant Sci. 2025 Dec 09. pii: S1360-1385(25)00331-0. [Epub ahead of print]

Communication between chloroplasts and the endoplasmic reticulum in plants under abiotic stress.

Thomas Depaepe, Sergi Munné-Bosch.

  Chloroplasts and the endoplasmic reticulum (ER) are vital organelles for plant cellular function, yet their communication remains relatively underexplored. Beyond photosynthesis and protein folding, both organelles serve as metabolic hubs and stress sensors, and their crosstalk represents a crucial missing link in plant stress biology. The discovery of membrane contact sites (MCSs) underscores this interdependence, revealing exchanges of biomolecules such as lipids that sustain cellular homeostasis. Evidence also points to stress metabolites, secondary messengers, and hormones as possible mediators in communication, particularly under adverse conditions. By discussing established and putative signals and pointing to emerging technologies, we show that ER-chloroplast communication is critical to understanding abiotic stress adaptation and may open new avenues for improving crop resilience in a changing climate.

Keywords:  ER–chloroplast signaling; lipid-derived signaling; membrane contact sites (MCSs); organelle communication; retrograde signaling; stress tolerance

DOI:  https://doi.org/10.1016/j.tplants.2025.11.009
Protein Cell. 2025 Dec 08. pii: pwaf109. [Epub ahead of print]

Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis.

Yanan Lv, Xuejing Zhao, Di Li, Zhaoqi Hao, Yue Zhao, Yuhang Zhou, Yujing Zhang, Han Chen, Zhongbing Lu, Dong Li, Yuting Guo.

  Mitochondrial calcium fluxes serve as pivotal regulators of optimal organellar function and cellular viability, yet the spatiotemporal regulation of nanodomain Ca2+ transients at mitochondria-ER contact sites (MERCS) and their integration into adaptive mitochondrial stress signaling remain unresolved. In this study, we employed custom-built high temporal-spatial resolution GI/3D-SIM imaging techniques to achieve nanoscale resolution of calcium transients. We identify that MERCS-localized calcium oscillations gate retrograde stress signaling. Mechanistically, we demonstrate that augmented mitochondria-associated ER membrane (MAMs) connectivity unexpectedly attenuated global mitochondrial Ca2+ efflux, which triggering ATF5 shuttling-mediated transcriptional licensing and calcium-sensitive epigenetic reprogramming that synergistically activating stress-resilience programs. Quantitative protein expression and transcriptome analyses confirm that CsA-mediated calcium retention mimics MAMs induction preserves mitochondrial integrity and protecting cells from apoptosis in Aβ1-42-challenged neurons through synchronized UPRmt activation. Our findings reveal a novel mechanism by which MERCS decode proteotoxic stress into transcriptional and epigenetic adaptations, offering therapeutic potential for neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Mito-ER interaction; calcium transients; mitochondrial stress response; super-resolution microscopy

DOI:  https://doi.org/10.1093/procel/pwaf109
Zhonghua Jie He He Hu Xi Za Zhi. 2025 Dec 12. 48(12): 1196-1202

[Research advances on mitochondria-associated endoplasmic reticulum membrane in pulmonary hypertension].

L Q Qi, Z F Xue, X S Liu.

Pulmonary hypertension (PH) is a complex disease characterized by progressive elevation of pulmonary arterial pressure and pulmonary vascular remodeling, which is notoriously difficult to treat and often leads to right heart failure and poor long-term prognosis. Accumulating evidence indicates that the physical connection between the endoplasmic reticulum and mitochondria forms specialized domains known as mitochondria-associated endoplasmic reticulum membrane (MAM). Aberrations in the quantity, structure, or function of MAM are closely associated with the pathogenesis and progression of PH. This review systematically summarizes the structural features and multifunctional roles of MAM in the pathophysiological processes of PH, with a particular focus on the molecular mechanisms by which MAM regulate key biological processes, including calcium homeostasis, mitochondrial biogenesis, mitochondrial dynamics, and endoplasmic reticulum stress. The aim is to provide a scientific basis for understanding the role of MAM in PH and to identify novel therapeutic targets.

DOI: https://doi.org/10.3760/cma.j.cn112147-20250620-00344
Genetics. 2025 Dec 12. pii: iyaf267. [Epub ahead of print]

Hinge sites in the lipid transfer channel modulate function of the yeast bridge-like transfer protein Vps13.

Jae-Sook Park, Hoang Nguyen, Mary Hongying Cheng, Ivet Bahar, Aaron M Neiman.

  Vps13 transporters are large, rod-shaped proteins that mediate the bulk transfer of lipids between intracellular membranes via a hydrophobic channel formed by multiple "repeating beta-groove" (RBG) domains. Gain-of-function mutants in yeast Vps13 bypass the need for phospholipid trafficking by the endoplasmic reticulum-mitochondrion contact site complex ERMES. This work shows these same mutants can partially compensate for defects in lipid transfer at a different membrane contact site, suggesting that these VPS13 alleles encode a protein that is more efficient than wild type Vps13 at lipid transfer. The gain-of-function mutations map to similar positions on different RBG repeats within the predicted Vps13 structure. Computational modeling of the structural dynamics of individual RBG repeats indicates that these mutations are biased to regions that act as hinges within the protein. We propose that lipid transport by Vps13 involves cycling between conformational states and that these mutants increase lipid transport by altering the dynamics of this conformational shift.

Keywords:  gain-of-function; lipid transport; sporulation

DOI:  https://doi.org/10.1093/genetics/iyaf267
J Microsc. 2025 Dec 12.

Integrated approaches for multiscale mitochondrial structure and function analysis.

Adiba Patel, Prasanna Venkhatesh, Suraj Thapliyal, Margaret Mungai, Leo Jake Kazma, Muhammad Aftab, Antentor Hinton, Prasanna Katti.

  Mitochondria are double-membrane organelles whose architecture enables ATP (Adenosine Triphosphate) production, redox signalling, calcium homeostasis, and apoptosis. Visualisation of mitochondria requires imaging technologies across spatial and temporal scales. Conventional fluorescence microscopy techniques, such as wide-field, confocal, spinning-disk, and light-sheet microscopy, enable the real-time observation of mitochondrial networks and dynamics in live cells. Super-resolution methods, including structured illumination microscopy (SIM), stimulated emission depletion microscopy (STED), photoactivated localisation microscopy (PALM), stochastic optical reconstruction microscopy (STORM), and expansion microscopy, provide access to fine sub-mitochondrial structures, such as cristae, overcoming the diffraction limit. Additionally, proximity-based approaches such as FRET (Förster Resonance Energy Transfer), split-fluorescent proteins, and proximity ligation assays allow researchers to probe sub-compartmental interactions and organelle contact sites with nanometre-level sensitivity. Electron microscopy (EM) complements optical techniques by offering near-molecular resolution of mitochondrial ultrastructure, including membranes, cristae, and inter-organelle interfaces. In this review, we comprehensively examined the principles, capabilities, and limitations of these diverse imaging modalities, with a focus on recent advances. We highlight the development of novel fluorescent probes, integrated correlative techniques, and computational analysis pipelines to expand the utility of mitochondrial imaging. By placing these innovations in historical and theoretical contexts, we aim to clarify how each method works and why it is suited to biological questions. Finally, we explore how mitochondrial imaging has revolutionised our understanding of physiology and pathology.

Keywords:  cristae; electron microscopy; membrane contact site; mitochondria; organelle dynamics; super‐resolution microscopy

DOI:  https://doi.org/10.1111/jmi.70050
Nat Commun. 2025 Dec 10. 16(1): 11010

GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.

Gregory Austin, Affiong I Oqua, Liliane El Eid, Mingli Zhu, Yusman Manchanda, Priyanka Peres, Helena Coyle, Yelyzaveta Poliakova, Zhanna Balkhiyarova, Karim Bouzakri, Alex Montoya, Dominic J Withers, Michele Solimena, Ben Jones, Steven J Millership, Steffen Burgold, David C A Gaboriau, Endre Majorovits, Evelyn Garlick, Maria Augusta do R B F Lima, Inga Prokopenko, Jonathon Nixon-Abell, Andreas Müller, Alejandra Tomas.

Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic β-cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and β-cell functional adaptation. Here, we present a comprehensive study in β-cell lines and primary islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic reticulum (ER) membrane contact site (MCS) tether VAPB at ER-mitochondria MCSs (ERMCSs), where active GLP-1R engages with SPHKAP, an A-kinase anchoring protein (AKAP) previously linked to T2D and adiposity risk in genome-wide association studies (GWAS). The inter-organelle complex formed by endosomal GLP-1R, ER VAPB and SPHKAP triggers a pool of ERMCS-localised cAMP/PKA signalling via the formation of a PKA-RIα biomolecular condensate which leads to changes in mitochondrial contact site and cristae organising system (MICOS) complex phosphorylation, mitochondrial remodelling, and β-cell functional adaptation, with important consequences for the regulation of β-cell insulin secretion and survival to stress.

DOI: https://doi.org/10.1038/s41467-025-66115-x
Free Radic Biol Med. 2025 Dec 08. pii: S0891-5849(25)01420-0. [Epub ahead of print]244 133-146

Prepuberty exposure to polystyrene nanoplastics induces cardiac inflammation through calcium overload-mediated ROS/JAK1/STAT3 signaling cascade.

Wei Liu, Yang Liu, Jin Shi, Jiajin Li, Gu Li, Junjun Quan, Weian Zhao.

  Polystyrene nanoparticles (PS-NPs) pose a significant threat to human health. In the present study, we aimed to investigate the toxicological effects of low-dose of PS-NPs on cardiac development and function following prepubertal exposure. Postpartum dams and their offspring were exposed to PS-NPs at concentrations of 0, 50 mg/L, and 100 mg/L via their daily drinking water, commencing from gestational day 1 and continuing until postnatal day (PND) 35. The results demonstrated that PS-NPs induced cardiac developmental toxicity in offspring. Proteomic analysis indicated that PS-NP exposure led to differentially expressed proteins, which were mainly enriched in JAK/STAT3 signaling pathway, inflammatory response pathway and antioxidant response signaling pathway. We subsequently found that exposure to PS-NPs in HL-1 cells increased the levels of reactive oxygen species (ROS), IL-6, IL-17, and TNF-α, as well as upregulated the expression of pJAK1 and pSTAT3. Treatment of HL-1 cells with N-Acetylcysteine (NAC) normalized the activity of the JAK1/STAT3 pathway and the levels of inflammatory cytokines. Furthermore, either inhibition of JAK1 with upadacitinib or knockdown of STAT3 in PS-NP-exposed HL-1 cells led to proinflammatory cytokine levels comparable to those in control cells. Given the well-established link between oxidative stress and mitochondrial calcium dysregulation, we demonstrated that PS-NP exposure impaired mitochondrial function by promoting calcium influx, which is mediated by the increased formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). This process facilitated calcium transfer through the IP3R3-GRP75-VDAC1 complex. Notably, pharmacological inhibition of calcium flux attenuated PS-NP-induced mitochondrial dysfunction, oxidative stress, and inflammatory responses in HL-1 cardiomyocytes. Collectively, our findings indicate that prepubertal PS-NP exposure triggers cardiac inflammation, which is likely mediated by MAM-dependent mitochondrial calcium overload and subsequent activation of the ROS/JAK1/STAT3 signaling axis.

Keywords:  JAK1/STAT3; MAM; PS-NPs; ROS; cardiac inflammation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.006
Int J Biol Sci. 2026 ;22(1): 43-59

Dual-pathway mechanism of vanadium-induced hepatotoxicity in ducks: Synergistic crosstalk between glucose homeostasis disruption and NADH/FSP1/COQ10 axis-driven ferroptosis.

Huawei Chen, Xueyan Dai, Zhiwei Xiong, Huabin Cao, Chenghong Xing, Haotang Li, Xiaona Gao, Mingwen Hu, Fan Yang.

  In intensive duck production systems, vanadium (V) is widely used as a growth-promoting additive, but excessive supplementation poses health risks to ducks. Previous research indicated that V could cause damage to organs by disrupting the structure and function of mitochondria and the endoplasmic reticulum. However, the precise mechanism of mitochondrial-associated endoplasmic reticulum membranes (MAMs) in V-induced hepatotoxicity remains unclear. To fill this gap, this study employed network toxicology to analyze the hepatotoxicity of V, and further validated the pivotal roles of glucose homeostasis and ferroptosis in this process through targeted MAMs proteomics. The results indicated that V exposure increased liver dysfunction markers, disrupted hepatic cord structure, and widened ER-mitochondria gaps. Besides, V exposure up-regulated the levels of the IP3R-Grp75-VDAC1 complex in MAMs while promoting its dissociation. Moreover, the sequencing results of MAMs demonstrated that V primarily induced hepatotoxicity by disturbing the glycolysis/gluconeogenesis pathway. Notably, V exposure exacerbated lipid peroxides and Fe2+ accumulation while inhibiting the NADH/FSP1/CoQ10 axis, down-regulating the expression levels of ferroptosis-related factors in livers. These findings demonstrated that dietary V overexposure impaired hepatic MAMs integrity, disrupted glucose homeostasis, and suppressed the NADH/FSP1/CoQ10 axis, which ultimately induced ferroptosis-mediated liver injury in ducks.

Keywords:  MAMs proteomics; NADH/FSP1/CoQ10 axis; ferroptosis; glucose homeostasis; vanadium

DOI:  https://doi.org/10.7150/ijbs.123482
Animals (Basel). 2025 Dec 01. pii: 3465. [Epub ahead of print]15(23):

Crosstalk Between the Endoplasmic Reticulum and Mitochondria in Skeletal Muscle: Implications for Meat Quality.

Wenjin Peng, Yiting Guo, Xiaolin Wu, Liuteng Miao, Xihong Zhou.

  The coordination between the endoplasmic reticulum (ER) and mitochondria is increasingly recognized as a central regulator of skeletal muscle metabolism and, consequently, meat quality. Here, we summarize recent progress on how ER-mitochondrial communication regulates muscle metabolism and meat-quality traits. This interaction, primarily mediated by mitochondria-associated membranes, integrates key cellular processes, including calcium signaling, redox homeostasis, lipid metabolism, and cellular stress responses. These events then lead to tissue-level outcomes such as intramuscular fat deposition, transitions in muscle fiber types, and postmortem apoptotic or proteolytic events, all of which influence meat quality. However, comparative studies across livestock species reveal notable gaps and inconsistencies, highlighting the need for deeper mechanistic investigation. Overall, deepening our understanding of ER-mitochondria crosstalk will inform nutritional or molecular strategies to enhance meat quality and clarify species-specific regulatory mechanisms.

Keywords:  endoplasmic reticulum; meat quality; mitochondria; mitochondria-associated membranes

DOI:  https://doi.org/10.3390/ani15233465
Food Res Int. 2026 Jan;pii: S0963-9969(25)02266-5. [Epub ahead of print]223(Pt 1): 117928

EGCG attenuates Cd reproductive toxicity in Caenorhabditis elegans by modulating ER-mitochondrial interactions.

Shuanghui Wang, Siyu Zheng, Yushun Gong, Junhe Hu, Yong Chen.

  The effect of epigallocatechin gallate (EGCG), a natural catechin derived from tea, on mitigating cadmium (Cd)-induced reproductive toxicity in animal models remains incompletely understood. In this study, an in-depth investigation into the effect of EGCG on the reproductive capacity of Caenorhabditis elegans under Cd exposure was conducted. Our findings revealed that EGCG significantly mitigated the Cd-induced decline in the brood size of C. elegans. The biological mechanisms were found to be associated with the endoplasmic reticulum unfolded protein response (UPRER) and mitochondrial unfolded protein response (UPRmt), suggesting a role for ER-mitochondrial interactions in the detoxification process. Further investigation revealed that EGCG mitigates Cd-induced reproductive toxicity by modulating the calcium channel protein VDAC-1 at the ER-mitochondrial contact sites. Thus, our findings provide mechanistic insights into the potential detoxifying effects of tea.

Keywords:  Cadmium; Tea; Tea polyphenols; Unfolded protein response

DOI:  https://doi.org/10.1016/j.foodres.2025.117928
Theranostics. 2026 ;16(3): 1410-1431

PINK1/Parkin promotes liver regeneration via Sigma-1 ubiquitination to inhibit ER-Mitochondrial calcium transfer.

Jian Xu, Yuechen Wang, Weizhe Zhong, Haoran Hu, Ye Zhang, Yiyun Gao, Ping Wang, Zhuqing Rao, Haoming Zhou, Xuehao Wang.

  Rationale: Liver regeneration is regulated by both metabolic processes and immune responses. Nonetheless, there is limited comprehension of the mechanisms involved. PINK1/Parkin-mediated mitophagy has been well documented, the role and underlying alternative mechanism of PINK1/Parkin in regulating mitochondrial metabolism during liver regeneration remains unclear. Methods: Liver tissues from mice undergoing hepatectomy were utilized to evaluate the expression levels of PINK1/Parkin. Hepatocyte-specific PINK1 knockout and transgenic mouse models were generated to investigate the impact of PINK1 on regeneration. Mass spectrometry, co-immunoprecipitation, and ubiquitination assays were performed to explore the underlying molecular mechanisms. Results: We observed PINK1/Parkin expression was markedly upregulated in hepatic tissue following liver resection. PINK1 depletion in hepatocytes caused impaired liver regeneration. Moreover, mitochondrial calcium overload was found be responsible for restricted TCA by inhibiting succinate dehydrogenase activity in PINK1 deficient hepatocytes. Interestingly, PINK1 deficiency leads to succinate accumulation and release from hepatocytes, which impairs liver regeneration by restricting macrophage pro-repair phenotypes. This effect was further confirmed by enhanced regeneration in myeloid SUCNR1 knockout mice. Mechanistically, Sigma-1 is a molecular chaperone of the endoplasmic reticulum calcium channel IP3R, which helps maintain its normal functional conformation. Parkin was able to bind Sigma-1 through its UBL domain, facilitating its k48-linked ubiquitination, which promotes Sigma-1 degradation and subsequently suppressing calcium transfer from the ER to mitochondria at the mitochondrial-associated ER membrane. Conclusions: Collectively, PINK1/Parkin signaling regulates hepatocellular mitochondrial ATP and succinate production by modulating ER-mitochondria calcium transfer to promote liver regeneration, revealing a promising therapeutic target for liver regeneration.

Keywords:  MAM calcium channel; PINK1/Parkin; liver regeneration; sigma-1; succinate

DOI:  https://doi.org/10.7150/thno.115726
Phytomedicine. 2025 Nov 22. pii: S0944-7113(25)01224-3. [Epub ahead of print]150 157589

MARCH5-mediated MIEF2 ubiquitination and degradation contribute to gigantol to against hepatic steatosis and mitochondrial fission in alcoholic liver disease.

Yangsheng Wu, Shijie Dai, Zheming Li, Lanman Xu, YuJia Zhang, Jiannan Qiu, Lin Chen, Yiyou Lin, Mingjiang Mao, Jianglei Xu, Shouye Li, Xiaofeng Yuan, Xiaobing Dou.

   BACKGROUND: Alcoholic liver disease (ALD) is among the most prevalent health issues caused by chronic alcohol consumption. The mitochondrial E3 ligase Membrane Associated Ring-CH-type Finger 5 (MARCH5, also known as MITOL) is involved in mitochondrial fission in ALD. Gigantol (Gig) has been reported to alleviate oxidative dysfunction and inflammation in liver injury, but its effects on ALD and the mechanisms underlying these effects are not completely comprehended. This study aimed to explore the potential effects and mechanisms of Gig against ALD.
METHODS: In this research, we explored the impacts of Gig on ethanol-treated zebrafish larvae, C57BL/6 mice, and AML12 cells. In vitro and in vivo gain- and loss-of-function experiments were employed to investigate the functions of MARCH5 and MIEF2 in ALD and the mechanisms underlying their functions.
RESULTS: Gig alleviated hepatic steatosis, cell death, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial fission in both animal and cell models. Functionally, MIEF2 depletion potently repressed fatty acid synthesis, cell apoptosis and mitochondrial fission in vitro, at least in part by inhibiting the ROS/JNK/CHOP pathway. Moreover, overexpression of MIEF2 effectively reversed the reduction in lipid accumulation, cell death, mitochondrial fission, and mitochondria-associated membrane (MAMs) formation caused by MARCH5 overexpression. Mechanistically, MARCH5 directly interacted with MIEF2 to cause its ubiquitination and proteasomal degradation, thereby regulating mitochondrial dynamics in AML12 cells. Additionally, liver-specific MARCH5 knockdown markedly aggravated liver injury induced by an ethanol-containing diet. Importantly, liver-specific knockdown of MARCH5 in ALD model mice abolished the protective effects of Gig on the liver, partly through the activation of the MIEF2/JNK/CHOP pathway.
CONCLUSION: These results suggest that Gig may protect against hepatic steatosis and mitochondrial fission in ALD by targeting MARCH5 to mediate ubiquitination and degradation of MIEF2, which lays the foundation for research on the effects of Gig against liver illnesses.

Keywords:  Alcoholic liver disease; Gigantol; MARCH5; MIEF2; Mitochondrial fission; Ubiquitination

DOI:  https://doi.org/10.1016/j.phymed.2025.157589
Cell Signal. 2025 Dec 08. pii: S0898-6568(25)00713-2. [Epub ahead of print]139 112298

ED-71 prevents glucocorticoid-induced bone loss by inhibiting type H vascular endothelial cell senescence through maintaining mitochondria-associated membrane-mediated calcium homeostasis.

Xiaorui Wang, Weidong Zhang, Ting Liu, Xing Rong, Qinghua Ren, Shibing Guan, Minqi Li.

  Glucocorticoids (GCs) are widely used in anti-inflammatory and immunosuppressive therapies. However, long-term or high-dose administration of GCs often leads to bone loss, resulting in GC-induced osteoporosis (GIOP). GIOP reduces bone strength, increases fracture risk, and affects the quality of life and treatment compliance of patients. Therefore, there is an urgent need to develop new therapeutic drugs for GIOP. This study found that the active vitamin D analog eldecalcitol (ED-71) can prevent GIOP by inhibiting vascular endothelial cells (ECs) senescence and improving angiogenesis and osteogenesis. Dexamethasone (DEX) induces senescence of type H vascular ECs by promoting mitochondrial calcium overload mediated by mitochondrial-associated membranes (MAMs). ED-71 regulates glucose-regulated protein 75 (GRP75) through the vitamin D receptor (VDR)-protein kinase C (PKC) signaling pathway, reduces MAM-mediated mitochondrial calcium overload, inhibits senescence of ECs, and restores the angiogenesis-osteogenesis coupling mechanism, thereby ameliorating bone loss. This study reveals a new mechanism by which ED-71 ameliorates GIOP, by maintaining MAM-mediated mitochondrial calcium homeostasis to reduce vascular bone disease. This finding not only provides theoretical support for the application of ED-71 in the prevention and treatment of GIOP but also offers important theoretical basis for the development of MAM-targeted drugs for osteoporosis, as well as suggestions for potential therapeutic targets.

Keywords:  ED-71; GIOP; MAMs; Mitochondrial calcium overload; Senescence; Type-H blood vessel; Vascularized osteogenesis

DOI:  https://doi.org/10.1016/j.cellsig.2025.112298